The overall goal of this grant is to increase our understanding of the etiology of Functional Hypothalamic Amenorrhea (FHA) and test several novel treatment regimens for this reproductive disorder. Anovulation is the most common cause of infertility in women and FHA is the most common cause of anovulation. The proximate cause of FHA is insufficient hypothalamic gonadotropin-releasing hormone (GnRH) secretion. However, a constellation of neuroendocrine secretory disturbances attributable to altered hypothalamic function exist. Our current investigation in women and in monkeys implicates dysfunctional attitudes, psychosocial stress, and associated behaviors such as calorie restriction and exercise in the genesis of characteristic hypothalamic-pituitary-adrenal (HPA), HP-thyroidal (HPT), and HP-ovarian (HPO) secretory alterations. Thus, we conceptualize FHA as a state of altered hypothalamic homeostasis caused by synergism between psychogenic challenge and metabolic compromise. Building on these findings, we hypothesize that cognitive behavior therapy (CBT) aimed at improving attitudes and correcting problematic behaviors will reverse hypothalamic derangements and restore ovulation. One aim of this project is to test this hypothesis. However, because not all women with FHA will respond to CBT, we are continuing our quest to discern in women and in monkeys the neurobiological mechanisms underlying the synergism between psychogenic and metabolic stressors with the goal of identifying promising pharmacologic interventions. To refine our model of the pathogenesis of FHA, monkey studies are critical to identifying causality and pharmacologic options, while the human studies are integral to testing the efficacy of psychosocial and pharmacologic therapies. An interdisciplinary team of established investigators is working on these combined clinical and basic studies, with expertise in the areas of psychiatry, behavioral medicine, exercise physiology, neurobiology, and reproductive endocrinology.